1. Field of the Invention
The present invention relates to a process to manufacture sustained release tablets of a therapeutically active ingredient. More specifically, the present invention is a novel approach to prepare a micronized granulation containing both active and inactive ingredients which can be formulated into a sustained release tablet.
2. Description of the Prior Art
Both for the patient and the physician, sustained release dosage forms, in general, are a great advantage over immediate release dosage forms because they allow a therapeutically effective amount of an active ingredient to be continuously delivered over an extended period of time with a minimum number of daily doses, in some instances as few as one dose per day. A common approach to impart sustained release characteristics to a solid pharmaceutical formulation is to coat the active ingredient with a relatively insoluble coating, or to embed the active ingredient in a resinous matrix. The slow diffusion of drug, or erosion of the coating or the matrix then releases the active ingredient. Various approaches have been described in the patent literature, a representative sampling of which appears below.
U.S. Pat. No. 4,666,705, issued May 19, 1987, to De Crosta et al, describes a controlled release pharmaceutical formulation in the form of a tablet which includes an active agent and an acrylic acid polymer or copolymer. The tablet is formed via a dry granulation technique and does not require a coating.
U.S. Pat. No. 4,786,503, issued Nov. 22, 1988, to Edgren et al, describes a pharmaceutical dosage form having two lamina disposed adjacent one another to form a tablet. The lamina may contain both active and inactive ingredients such that the release characteristics of the resultant tablet may be controlled by the arrangement of the lamina. Each of the lamina are composed of at least one type of hydroxypropylmethyl cellulose. Celluloses having differing degrees of polymerization (DP) are also used to control release of the active agent. A related composition is described by Edgren et al in U.S. Pat. No. 4,871,548, issued Oct. 3, 1989.
U.S. Pat. No. 4,814,175 issued Mar. 21, 1989, to Tack et al, describes a combination pharmaceutical containing nifedipine and mepindolol. The nifedipine and mepindolol are granulated separately using conventional excipients via a wet or dry granulation process. The separate granules are then placed within hard gelatin capsules for oral consumption.
U.S. Pat. No. 4,882,144, issued Nov. 21, 1989; and the resulting Reissued Patent, U.S. Pat. No. 33,963, issued Jun. 16, 1992 to Hegasy; as well as U.S. Pat. No. 5,264,446, issued 23, 1993, to Hegasy et al, describe a solid pharmaceutical composition containing dihydropyridines, and processes for their production. Specifically, Hegasy describes the dissolution of nifedipine and polyvinylpyrrolidone (PVP) in a limited amount of organic solvent to form a viscous slush containing nifedipine and PVP. The slush is then mixed with a cross-linked, insoluble polyvinylpyrrolidone (PVPP) to cause agglomeration. This agglomerated mixture is then compressed into tablets in which the nifedipine (or other dihydropyridine active agent) is uniformly spread throughout the tablet.
Another pharmaceutical composition containing dihydropyridines, PVP and insoluble PVPP is described by Schmidt et al in U.S. Pat. No. 5,266,581, issued Nov. 30, 1993. Here, the dihydropyridine and the PVP are dissolved in a suitable organic solvent, and a wetting agent is added thereto. Insoluble PVPP is then added to the mixture, and the mixture is granulated. The granules so formed are then further processed into tablets with the inclusion of various conventional additives.
U.S. Pat. No. 4,952,402, issued Aug. 28, 1990, to Sparks et al, describes a controlled release powder for edible and pharmaceutical formulations. The composition includes micro-particles of a pre-determined size (0.1 to 125 micrometers) which define a matrix of an inert polymer with an active agent uniformly dispersed therein. The dissolution rate of the inert polymer matrix causes the sustained release of the active agent.
U.S. Pat. No. 5,108,757, issued Apr. 28, 1992, to Erdos et al describes a process similar to Schmidt et al, above, except that instead of directly granulating the PVP/nifedipine mixture with insoluble PVPP, wetting agents and retarding agents are added to a PVP/nifedipine slush, and the slush is coated onto inert carrier particles. The coated carrier particles are then dried and sieved. The coated particles themselves are then admixed with conventional additives and either compressed into tablets and coated, or placed inside conventional capsules. Erdos et al assert that, because the grinding and milling of the active ingredient is eliminated in this process, the particle size distribution and particle structure of the starting bulk material has no effect on the release profile of the product tablet. However, it should be noted that the particle size distribution and structure of the carrier particles onto which the active ingredient is coated will add statistical fluctuations to the release profile of the finished product.
Similar pharmaceutical compositions and methods are described in the following foreign patent documents: West German Patents No. DE 28 22 882, issued December 1978, and No. DE 31 42 853, issued May 1983; EPO Patents No. 0 047 899, issued March 1982, and No. 0 078 430, issued May 1983; Japanese Patent No 58-109-412, issued June 1983; and Great Britain Patent No. 2 139 892 A, issued November 1984. These foreign patent references are believed to be cumulative to the above-discussed U.S. patent references.